First symptoms use to manifest in early infancy. The absence of mature osteoclasts interferes with skeletal growth, including, but not limited to, the development of the skull. Children may be macrocephalic [1]. In any case, anomalies of skull growth adversely affect the development of the central nervous system, and infants are likely to present signs and symptoms of mental and motor retardation [2]. Furthermore, excessive bone tends to obturate cranial nerve foramina and provoke cranial nerve palsy. The optic foramina are most commonly affected, and the majority of OPTB7 patients presents with progressive visual impairment due to optic nerve compression. Vision loss results in blindness, and blindness may even be congenital [1]. Nystagmus is another common finding.

Medullary cavities are likewise filled up with bone tissue, inducing a shift of hematopoiesis from the marrow to the liver and spleen. Hepatosplenomegaly is the clinical equivalent of this process and may entail gastroesophageal reflux [1], but the patients' body is not usually able to compensate for the loss of bone marrow spaces. Cytopenias may ensue. Those suffering from anemia may present with pallor and chronic fatigue, while thrombocytopenia gives rise to a hemorrhagic diathesis. Leukopenia may account for increased susceptibility to infection and is observed in several types of autosomal recessive osteopetrosis. In OPTB7, however, immunodeficiency is aggravated by a second mechanism inherent to B-cell function: The patients' antibody response is largely impaired, and laboratory analyses of blood samples may reveal severe hypogammaglobulinemia, even in the presence of normal lymphocyte counts. Accordingly, affected children may have recurrent infections, often severe, sometimes life-threatening. Pneumonia is a dreaded complication of OPTB7, and respiratory disorders have repeatedly been named as a cause of death [1] [2]. It shall be mentioned, though, that the immunological features of OPTB7 are variable and may possibly change over the course of the disease [1].

The underlying disorder of bone remodeling may entail electrolyte imbalances and thus a variety of additional symptoms. In this context, several patients have been reported to suffer from hypotonia and seizures, cardiac and respiratory arrest.

• Anemia

  Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. [uniprot.org]

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

• Short Stature

  Depending on severity and age of onset, features may includefractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures ,and life-threatening pancytopenia. [monarchinitiative.org]

  Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. [malacards.org]

  These patients may have a disproportionaly short stature, dental abnormalities, recurrent mandibular osteomyelitis, macrocephaly and strabismus. [healio.com]

• Developmental Delay

  Previously existing developmental delays and visual impairment, however, could not be reversed. [symptoma.com]

  delay 0001263 Growth delay Delayed growth Growth deficiency Growth failure Growth retardation Poor growth Retarded growth [ more ] 0001510 Hepatomegaly Enlarged liver 0002240 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 Hypocalcemic [rarediseases.info.nih.gov]

• Poor Growth

  growth Retarded growth [ more ] 0001510 Hepatomegaly Enlarged liver 0002240 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 Hypocalcemic seizures Low calcium seizures 0002199 Increased head circumference 0040194 Motor delay 0001270 Multiple [rarediseases.info.nih.gov]

• Increased Susceptibility to Infections

  susceptibility to infections and, in certain conditions, an icreased rate of malignancies and autoimmune disorders. [books.google.de]

  Leukopenia may account for increased susceptibility to infection and is observed in several types of autosomal recessive osteopetrosis. [symptoma.com]

  susceptibility to infections is an autosomal recessive disorder due to inactivating mutations in TBCE encoding tubulin specific chaperone E; this disorder may be genetically heterogeneous, however [37–39]. [content.iospress.com]

• Mild Clinical Course

  One OPTA2 patient displaying life-threatening symptoms died, and the OPTB4 patient presenting a relatively mild clinical course survived. [tandfonline.com]

• Malocclusion

  She had a heavy malocclusion with hypodontia, several impacted teeth, enamel dysplasia, and malformed teeth (Figure 1b). [nature.com]

• Hip Pain

  Eighteen months after implant removal, the patient reported left hip pain. Locally, no signs of infection or discharge were observed. Laboratory findings however, showed ESR 112/h, WBC 12000/mm3, and CRP 27. [healio.com]

• Normal Hearing

  She had normal hearing, but she had mild bilateral visual impairment due to atrophy of the bilateral optic nerves. Asymmetrical deformity of the fractured leg had not significantly progressed. [nature.com]

  One case of fatal encephalitis. [109] Some cases with spasticity, cognitive delay or deficits, and/or developmental delay, and cerebral calcifications (late-onset). [109] [110] Normal hearing. Recurrent or frequent otitis media. [autoinflammatory-search.org]

• Progressive Loss of Vision

  loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Proptosis Bulging eye Eyeballs bulging out Prominent eyes Prominent globes Protruding [rarediseases.info.nih.gov]

• Progressive Loss of Vision

  loss of vision Progressive vision loss Progressive visual impairment Slowly progressive visual loss Vision loss, progressive Visual loss, progressive [ more ] 0000529 Proptosis Bulging eye Eyeballs bulging out Prominent eyes Prominent globes Protruding [rarediseases.info.nih.gov]

• Abnormal Eye Movement

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

  The patients may have abnormal eye movements or nystagmus3. More rarely, the auditory, facial, and ol factory nerves may be affected4,2. The patient manifested symptomatic hypocalce mia since birth. [scielo.conicyt.cl]

• Psychomotor Retardation

  retardation 0025356 Recurrent pneumonia 0006532 Splenomegaly Increased spleen size 0001744 Thrombocytopenia Low platelet count 0001873 Showing of 25 Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]

• Seizure

  Depending on severity and age of onset, features may includefractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures ,and life-threatening pancytopenia. [monarchinitiative.org]

  Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. [malacards.org]

  Low calcium seizures 0002199 Increased head circumference 0040194 Motor delay 0001270 Multiple rib fractures 0006640 Nystagmus Involuntary, rapid, rhythmic eye movements 0000639 Optic atrophy 0000648 Optic nerve compression 0007807 Osteopetrosis Harder [rarediseases.info.nih.gov]

• Nystagmus

  Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) [orpha.net]

  Affiliated tissues include bone and bone marrow, and related phenotypes are decreased antibody level in blood and nystagmus Disease Ontology : 12 An osteopetrosis characterized by autosomal recessive inheritance that has material basis in homozygous or [malacards.org]

  ] 0001510 Hepatomegaly Enlarged liver 0002240 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 Hypocalcemic seizures Low calcium seizures 0002199 Increased head circumference 0040194 Motor delay 0001270 Multiple rib fractures 0006640 Nystagmus [rarediseases.info.nih.gov]

The diagnosis of osteopetrosis is based on diagnostic imaging [3]. Increased bone density can be recognized within the first months of life, and alternating lucent bands may be seen in the metaphyses of appendicular bones. Moreover, multiple fractures may be observed. Neuroimaging may reveal the causes of cranial nerve palsies and vision loss, namely the atrophy of the respective nerves due to bone compression. Additional anomalies may or may not be present; ventricular enlargement and Chiari malformation type 1 have been reported [1] [2].

The histological examination of bone and bone marrow biopsy specimens reveals the retention of large areas of cartilage, thickened trabecular bone with reduced resorption lacunae and very few osteoclasts, as well as narrowing of medullary cavities [3]. There may be abundant stem cells in the scarce marrow spaces, but reduced cellularity has also been described. In sum, the absence of multinucleated and active osteoclasts in excessively dense osseous tissue allows for the diagnosis of an osteoclast-poor form of osteoporosis [2].

There are two types of osteoclast-poor osteopetrosis, both of which involve abnormalities in the same signaling pathway: autosomal recessive osteopetrosis 2 and OPTB7 [1]. The diagnosis of OPTB7 thus has to be confirmed by means of genetic studies [3].

• Increased Bone Density

  Homepage Rare diseases Search Search for a rare disease Osteopetrosis-hypogammaglobulinemia syndrome Disease definition Osteopetrosis-hypogammaglobulinemia syndrome is an extremely rare primary bone dysplasia with increased bone density disorder characterized [orpha.net]

  Phenotype Severe form, osteoclast-poor, increased bone density (sclerosis) and generalized high bone mass, hypogammaglobulinemia. Main biochemical alterations: Adult/intermediate forms: high CK-BB, high bone ALP. [iofbonehealth.org]

  Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. [monarchinitiative.org]

  Osteopetrosis is a disorder of increased bone density due to defects in bone resorption. [ctgt.net]

Hematopoietic stem cell transplantation has been carried out in several OPTB7 patients and continues to be the recommended approach to therapy. In order to avoid irreversible sequelae, it should be realized as soon as possible. Guerrini and colleagues described a total of four children who underwent the procedure, two of which succumbed to complications, while the other two remained alive years after receiving their transplants [2]. The same team of scientists treated five more patients in the following years and could prevent mortality in this group. These patients were transplanted at different ages, the oldest child being 12 years old when undergoing the procedure, and were reported to be alive and reasonably well until the end of the study, at a maximum of 3 years after the transplantation. Previously existing developmental delays and visual impairment, however, could not be reversed [1].

OPTB7 patients are irresponsive to the administration of RANKL, since the differentiation of osteoclasts is interrupted downstream of the release of this cytokine. Even if available in excess, signals cannot be transmitted into the cell. Drugs aiming at rectifying the cause of growth failure would need to target elements situated even further downstream in the signaling cascade, but no such compounds have yet been used to manage OPTB7.

Hematopoietic stem cell transplantation has been shown to resolve the radiological features of osteopetrosis [1] [2]. Unfortunately, though, damage to nervous structures is largely irreversible. Patients are unlikely to compensate for developmental delays and improvements in vision are not to be expected [2]. Similarly, stem cell transplantations will not necessarily reverse skeletal deformities and induce compensatory growth [4]. The procedure itself is related to significant morbidity and mortality, with hypercalcemia, nephrocalcinosis, respiratory distress, and fractures being most frequently observed during follow-ups. The former may be related to the compensatory overexpression of RANKL [1].

Little is known about the long-term prognosis of OPTB7 patients who do not receive stem cell transplants. Individual patients have been described to live for years without presenting recurrent infections, while others died in infancy or childhood [2]. These observations support the hypothesis of phenotypic variability in OPTB7 [1].

OPTB7 is caused by mutations in the TNFRSF11A gene. TNFRSF11A is located on the long arm of chromosome 18 and encodes for member 11A of the superfamily of tumor necrosis factor receptors. This receptor is involved in the development of osteoclasts and lymph nodes, and has been shown to regulate the interaction between T cells and dendritic cells. Nonsense mutations, missense mutations, and the insertion of a single nucleotide into the TNFRSF11A gene have been described in OPTB7 patients, who may be homozygous or compound heterozygous for pathogenic variants of the gene. To date, a total of twelve TNFRSF11A mutations have been linked to OPTB7, and they have been identified in eleven families [1] [2].

Autosomal recessive osteopetrosis is a rare disease, the incidence of which has been estimated at 1 in 250,000 live births [5]. OPTB7, however, accounts for a very small share of these cases, with only about a dozen cases described in the literature. In detail, eleven families have been described to harbor pathogenic variants of the TNFSF11A gene, and these families originate from distinct parts of the world. Parental consanguinity has been noted in the majority of cases, but few mutations have been found in more than one family, so epidemiological data argue against a role of founder effects as they have been described for other types of autosomal recessive osteopetrosis [1] [2].

TNFRSF11A mutations have also been related to familial expansile osteolysis, expansile skeletal hyperphosphatasia, Paget disease of bone type 2, and dysosteosclerosis [6] [7]. There are significant differences between those diseases and OPTB7: While accelerated bone turnover, focal bone involvement, and dominant inheritance are attributed to the former, dysosteosclerosis and OPTB7 are generalized, sclerosing bone diseases inherited in an autosomal recessive manner [5]. The common denominator of these conditions is an imbalance between the formation and resorption of bone tissue, a disorder of RANKL-mediated osteoclastogenesis.

RANKL is short for RANK ligand, where RANK is another name for TNFRSF11A. RANKL is the main osteoclast differentiation factor and is expressed by osteoblasts and stromal stem cells, while RANK is to be found on the surface of osteoclasts and their precursors [1]. Binding of RANKL to RANK activates the RANK/RANKL/osteoprotegerin signaling pathway, promotes the differentiation of osteoclast precursors into multinucleated, active osteoclasts, and thus favors bone resorption over bone formation. In patients suffering from osteolytic disorders, TNFRSF11A mutations lead to increased constitutive RANK signaling. OPTB7 and dysosteosclerosis, by contrast, are related to loss-of-function mutations and a significant decrease of RANK-mediated actions [7].

Besides osteoclast differentiation, the RANK receptor is implied in signaling pathways within the immune system. When TNFRSF11A mutations were first linked to the disease, it has been hypothesized that OPTB7 patients suffer from a partial failure in peripheral B cell maturation. RANK was speculated to be involved in the process of Ig switch and antibody maturation, or in the formation of secondary lymphoid tissues [2].

Genetic counseling should be provided to affected families, but these are not usually identified until a child is diagnosed with OPTB7. Therefore, the consequent workup of suspect cases forms the basis of disease prevention. The identification of the underlying mutation(s) allows for prenatal diagnosis to be made in the course of the next pregnancy and opens up the possibility to reach an informed decision. Ideas on future therapies of OPTB7 also include the transplantation of hematopoietic stem cells in utero, and this procedure would have to rest on prenatal diagnosis [4] [8]. Beyond that, education about the risks of consanguineous marriage may prevent such circumstances from occurring.

Autosomal recessive osteopetrosis is a general term referring to a group of disorders associated with impaired bone resorption. Initially, all types of autosomal recessive osteopetrosis were assumed to be related to increased numbers of dysfunctional osteoclasts [4]. In recent years, however, several case reports were published that include somewhat surprising results of bone biopsies: There were virtually no osteoclasts in these patients' bone tissue, and these findings have been explained by a disorder of osteoclastogenesis.

The identification of distinct gene defects and their respective impact on osteoclast differentiation, maturation, and function has given rise to the current classification of autosomal recessive osteopetrosis [4] [9]. There are at least eight types of the disease, two of which are characterized by the absence of osteoclasts [1]. Extensions of the existing scheme are to be expected in the near future, when additional mutations are determined that may give rise to osteopetrosis: For about one-third of all cases of osteoclast-poor osteopetrosis, the etiology remains unknown [2].

OPTB7 has been linked to mutations in the TNFRSF11A gene in 2008, by an Italian team of scientists. Guerrini et al. associated OPTB7 with impaired RANK/RANKL signaling, which plays a key role in osteoclast differentiation and lymphocyte function [2].

Autosomal recessive osteopetrosis 7 (OPTB7) is a very rare disease, with only about a dozen cases being described until today. OPTB7 is a hereditary disorder caused by mutations in the TNFRSF11A gene. This gene encodes for a protein that is involved in the differentiation of osteoclasts and the production of antibodies by B cells:

• Growth requires a continuous adaptation of bone structures, a tight balance of the formation and resorption of osseous tissue. The main function of osteoclasts is the resorption of bone tissue, so any lack of osteoclasts induces an increase in bone density. This condition is called osteopetrosis.
• B cells are specialized lymphocytes. They should be able to produce antibodies to combat infections, but this process is impaired in OPTB7 patients. Those who are unable to produce antibodies are diagnosed with hypogammaglobulinemia.

Accordingly, those suffering from OPTB7 present with excessively dense, fragile bones and susceptibility to severe, sometimes life-threatening infections. Impaired bone remodeling also interferes with the development and function of the nervous system, giving rise to mental retardation, visual impairment, and possibly other neurological deficits.

The diagnosis of OPTB7 is based on diagnostic imaging, laboratory analyses, and genetic studies. While the former provide important clues as to the cause of the disease, each case should be confirmed by means of the identification of the underlying mutation. What's more, precise knowledge regarding the mutation of TNFRSF11A allows for genetic counseling and prenatal diagnosis to be made in a possible future pregnancy.

OPTB7 have successfully been treated with hematopoietic stem cell transplantation. This procedure, however, is related to significant morbidity and mortality and does not affect existing damage to the nervous system. Ideally, OPTB7 should be prevented. In this context, it should be beared in mind that consanguineous marriage is a major risk factor for OPTB7 and many other hereditary disorders, and, if this practice was abolished, most cases of OPTB7 could be avoided.

1. Pangrazio A, Cassani B, Guerrini MM, et al. RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations. J Bone Miner Res. 2012; 27(2):342-351.
2. Guerrini MM, Sobacchi C, Cassani B, et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet. 2008; 83(1):64-76.
3. Zustin J, Amling M, Crazzolara R, Butscheidt S, Schulz A, Oheim R. [Morphological characteristics of osteopetrosis]. Pathologe. 2018; 39(2):164-171.
4. Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int. 2009; 84(1):1-12.
5. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008; 42(1):19-29.
6. Guo L, Elcioglu NH, Karalar OK, et al. Dysosteosclerosis is also caused by TNFRSF11A mutation. J Hum Genet. 2018; 63(6):769-774.
7. Ralston SH. Juvenile Paget's disease, familial expansile osteolysis and other genetic osteolytic disorders. Best Pract Res Clin Rheumatol. 2008; 22(1):101-111.
8. Frattini A, Blair HC, Sacco MG, et al. Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero. Proc Natl Acad Sci U S A. 2005; 102(41):14629-14634.
9. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013; 9(9):522-536.